Chemically, benazepril is (3S)-1-(carboxymethyl-[[(1S)-1-(ethoxycarbony)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one of Formula II. Benazepril is a well-known long acting ACE inhibitor primarily for the treatment of hypertension and was reported for the first time in U.S. Pat. No. 4,410,520.
Benazepril and other ACE inhibitors can be prepared by reacting an appropriate ester of (R)-2-hydroxy-4-phenylbutyric acid with an appropriate amine under standard conditions well known in the art. For example, Urbach and Henning, Tetrahedron Left, 25, 1143 (1984), discloses a synthesis using trifluoromethanesulfonic ester of ethyl (R)-2-hydroxy-4-phenylbutyrate.
In Canadian Patent Nos. 1292236 and 1267903 is disclosed a process for preparing the triflate of Formula I. The method comprises reacting an α hydroxycarboxylic acid derivative with a trifluromethanesulfonating agent in an inert solvent such as methylene chloride in the presence of a base such as pyridine to afford the triflate of Formula I in 84.3% yield. The triflate prepared by the above method when used in the synthesis of benazepril in the laboratory does not give the desired yields of benazepril hydrochloride. In fact, a low overall yield of 46% of benazepril hydrochloride was obtained which is not acceptable at a commercial scale. The low yield is attributable to the formation of pyridinium salt, when trifluoromethanesulfonic anhydride and pyridine are combined.
To overcome the problem of the formation of pyridinium salts during triflate formation, pyridine was replaced with sterically hindered bases such as 2,6-di-tert-butyl-4-methylpyridine and 2,4,6-tri-substituted pyrimidines (for example, Peter J. Stang et al, Synthesis, 1980, p-283; A-Garcia Martinez et al, bid, 1990, p-881). The use of these bases is not practical on a commercial scale owing to the high cost involved.
In U.S. Pat. No. 4,785,089, it has been emphasized that aromatic p-nitro or halo sulfonic esters of ethyl (R)-2-hydroxy-4-phenylbutyrate give better results than the trifluoromethane sulfonic ester of ethyl (R)-2-hydroxy-4-phenylbutyrate when used in the synthesis of ACE inhibitors like benazepril. The process involves alkylation of benzofused lactam with p-nitro or halo sulfonic ester of (R)-2-hydroxy-4-phenylbutyrate at 75-80° C. for about 9 hours and results in an overall yield of benazepril hydrochloride as 83.5%. However, this process is also not completely satisfactory and is disadvantageous at a commercial scale because of low overall yield.
It is, therefore, desirable to solve the problems associated with the prior art and to provide an efficient process for the preparation and isolation of the triflate of Formula I which process improves the economics by resulting in higher yields of benazepril hydrochloride and less reaction time. The process is easy to handle at commercial scale and causes the removal of the excess pyridine and pyridinum salts without any difficulty.